Percutaneous, image-guided core needle biopsy is being increasingly used to diagnose breast lesions. Compared to surgical biopsy, this procedure is less invasive, less expensive, faster, minimizes deformity, leaves little or no scarring and requires a shorter time for recovery. However, core needle biopsy provides a limited sampling accuracy because only a few small pieces of tissue (for histological analysis) are extracted from random locations in the suspicious mass. The objective of the proposed research is to design a novel optical sensor based on fluorescence and diffuse reflectance spectroscopy to improve the sampling accuracy of core needle biopsy. The sensor will potentially be able to survey multiple sites without the need for tissue removal and provide accurate and immediate feedback of optimal tissue sites for biopsy. The outcome of the proposed work will test the following two central hypotheses: (a) there exists a systematic and significant difference in the fluorescence and diffuse reflectance spectra of malignant and non-malignant (normal, benign) breast tissues, and (b) these differences can be exploited for breast cancer detection via a core biopsy needle. The specific aims of the proposed work are: (1) to measure fluorescence excitation-emission matrices (EEMs) and diffuse reflectance spectra at several source-detector separations from breast tissues of patients undergoing breast cancer surgery, (2) to systematically identify a subset of the optical spectra, probe geometry and minimum signal-to-noise that display maximal differences between the normal, benign and malignant breast, and (3) use the knowledge derived from aims 1 and 2 to develop, characterize and validate a novel side-firing fiber-optic probe for breast cancer detection during core needle biopsy. The proposed work has a number of clinically significant implications. The optical sensor could potentially lead to fewer follow up procedures and fewer repeat biopsies in patients suspected to have breast cancer. Ultimately, the optical method may eliminate the need for surgical diagnosis of breast lesions altogether. Moreover, this technology could ultimately be used to guide in vivo therapeutic modalities such as laser ablation. The technology proposed in this application will be applicable to the detection of other deeply seated solid tumors, and the proposed clinical studies will serve as an important database for future technology development related to breast cancer detection.